Automated microscope slide read system

ABSTRACT

A system for reading microscope slides in an automated fashion.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional patentapplication Ser. No. 60/781,768, filed Mar. 13, 2006. The disclosure ofsuch application is hereby incorporated by reference in its entiretywhere appropriate for teachings of additional or alternative details,features, and/or technical background, and from which priority isasserted.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to a system for readingmicroscope slides in an automated fashion.

2. Description of the Related Art

Conventional biomedical microscopy generally has entailed laboriouspreparation of samples from a patient onto microscope slides followed bythe sequential evaluation of each slide by a microscopist to determineif the patient samples indicate a biomedical condition. The process ofevaluating slides is not only costly, but expends valuable time delayingtreatment of biomedical maladies that may be detected.

One means for improving the efficiency of microscopy is to automate theprocess of presenting the slides for analysis under the microscope. Apossible approach to this automation is taught by Georges in U.S. Pat.Nos. 4,248,498 and 4,367,915, both entitled Automatic Microscope Slide.The mechanism disclosed there includes the microscope slides removablyhoused in a storage magazine, and a first actuator mechanism whichremoves each slide, in succession, from the magazine. The slide thusremoved is directly positioned for microscopic viewing by an XYZ stage.After viewing, the slide is automatically replaced to its originalposition in the slide magazine by a second actuator. The magazine isrepositioned for access to the next slide, to be examined, and theprocess is repeated. The identification of the slide is determinedsolely by its location in the magazine. Any data associated with a givenslide is separately recorded and associated with the slide only by meansof reference to the slide's address location in the magazine. U.S. Pat.Nos. 4,248,498 and 4,367,915 do not address means for uniquelyidentifying slides which are not placed in their assigned locations orinsuring linkage of the slide with its separately recorded data.Further, the location of regions of interest on the slide are notdirectly addressable; position data is only determinable for the slideholder.

SUMMARY OF INVENTION

There is disclosed herein a system for improving the efficiency ofreading tissue sample slides.

In one embodiment there is disclosed a method in a computer system forautomating microscopic analysis of a plurality of data-encodedmicroscope slides having material of analytical interest depositedthereon, and stored in a slide cassette, the method comprising: (a)determining the number and position of microscope slides stored incassette; (b) causing one or more of slides in said cassette to beremoved from cassette; (c) downloading encoded data on each of slide(s)removed from cassette; (d) associating said downloaded encoded data witha set protocol for analysis of said material on said microscope slide.The encoded data may comprise data physically stored on the slide, or inelectronics associated with the slide.

In another embodiment, there is disclosed a slide magazine cassette forstoring microscope slides, the magazine comprising: (a) a housingcomprising a top surface, a bottom surface, and two side surfaces,surfaces defining a through-void there between; (b) a plurality ofpaired engagement structures attached to each of side surfaces ofhousing and projecting into thorough-void, each of paired engagingstructures being substantially parallel to another pair of engagingstructures attached to the antipodal side surface; wherein each ofparallel paired engaging structures are configured and spaced to allowfor the engagement and support of a single microscope slide between theengaging structures, and to permit movement of slide with respect to theengagement structures when a force is applied perpendicular to aparallel pair of engagement structures from either side of through-void.

The slides of such cassettes may be read by an automated unloadingmechanism. In one embodiment, there is disclosed a slide feeder formoving a slides housed in a microscope slide magazine/cassette. Moregenerically there is disclosed a slide feeder for moving a slide havinga top surface, a bottom surface and two or more lateral side surfaces(s)from a first location to a second location, the slide feeder comprising:a stage operatively configured to move in an x-y direction, and a slideengager coupled to the stage; the slide engager operatively configuredto hold the slide by pressure fit between two or more lateral surfacesof the slide.

The slide feeder may feed a slide to a stage for reading. In anembodiment of the invention the microscope comprises multiple stages. Inone embodiment, there is a first stage operatively configured to hold amicroscope slide and to move only along an x-y axis, as well as a secondstage operatively associated with the first stage and capable ofmovement only along the z⁻-z⁺ axis. In such embodiment movement of thesecond stage along such axis causes movement of the microscope slideheld by the first stage in the same direction.

Reading of the samples on the slides may be improved by incorporatingone or more coordinate reference points on the slides that aredetectable by the microscopy system. In one embodiment there isdisclosed an automated microscope slide analysis system for viewingmicroscope slides, the system comprising: (a) one or more microscopeslides having one or more electronically-addressable position tag(s)thereon; (b) a field objective operatively configured to allow viewingof a defined field on microscope slide; (c) an emitter operativelyconfigured to emit an electromagnetic wave toward at least one ofelectronically-addressable position tag(s); (d) a detector operativelyconfigured to detect at least one of position tag(s) from the responseof the tag to the electromagnetic wave, and a processor configured forprocessing information form the detector and the field objective todetermine the position of the field viewed or desired to be marked withrespect to at least one of the electronically-addressable positiontag(s).

In one embodiment, the slide is imaged by a microscope slide imagecapture system comprising: (a) a camera having at least one CMOSdetector and operatively configured to capture at least about 300 ormore images per second, (b) a plurality of sensors positioned to detectmovement of the microscope slide in x-y-z space during capture of eachimage, and a processor operatively configured to process images from thecamera and data from the plurality of sensors and to correct formovement of images during image capture by either altering the images ordiscarding the same.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of an embodiment of the slide magazine.

FIG. 2 is a schematic presentation of the inner surface of the firstside wall.

FIG. 3 is a perspective view of the first side wall.

FIG. 4 is a schematic view of the outer surface of the second side wall.

FIG. 5 is an end view of the second side wall showing the railstructure.

DETAILED DESCRIPTION OF THE INVENTION

Images gained by the microscopy system may be presented to a viewerthrough a graphical user interface. In one embodiment, there isdisclosed a graphical user interface in a microscopy system comprising:(a) a first portion graphically displaying the surface of a microscopeslide and the relative position of field of interest thereon; (b) asecond portion graphically displaying the field of interest in aplurality of magnifications; wherein the first and second graphicaldisplays are movable at least along the x and y axis.

In one embodiment there is disclosed microscope slides having encoded indigitally readable fashion thereon information pertaining to the originand desired processing of the tissue sample thereon. Encoding of thedata on the slide may be by any suitable means. Examples of such meansinclude recording the data in the form of bar codes, whether one- ortwo-dimensional (or otherwise), in the form of optical disuniformitiesrepresentative of digital data (e.g. in the form of pits and lands suchas found on a CD or DVD), or stored in an electronic tag on the slide(such as with REID, or other computer chip). The slide data encodationprocess may be selected so as to allow encoding of data on the fly inorder that information thought useful for processing could be added tothe slide as it is moved along the custody chain. For example, withrespect to a slide containing tissue from a patient, the encodedmicroscope slide might contain information including the name, address,age, sex, race, medical history of the patient, and may contain aclinical description of the physician ordered test, as well asinformation pertaining to the physician who requested the test, and thephysician or testing facility where the information obtained from thetests are to be forwarded. As the slide is read, preferably the meansfor storing data on the slide allows for information from the slide readto be added to the slide for future reference (for example, the date onwhich the slide was read, by what means the slide was read (e.g.automated microscopy system of x), the clinic that did the read, theresults of the read). The encode data may also comprise informationpertaining to the protocol selected for analysis of the material on theslide, and may store one or more images obtained with respect to thesample at points in time. Such images may be useful for adjudgingdegradation of sample. The data may be stored in a write-once read-many(WORM) memory for purposes of preventing overwriting of stored data orimages or, alternatively, in a memory that permits in whole or partoverwriting of data. An embodiment may permit the overwriting of onlyselect portions of the stored data.

The encodation on the slides on the cassette may be used to associatethe slide with the particular position in the magazine the slide wasoriginally placed. Using such information, when automated microscopy isused, the slide can be read, and the slide replaced in the same positionin the magazine, e.g. between the same engagement structures in which itwas once held.

When a set protocol for analysis has been provided for processing theslide, an automated method for review of the slide may be undertaken. Inone embodiment there is disclosed a method in a computer system forautomating microscopic analysis of a plurality of data-encodedmicroscope slides having material of analytical interest depositedthereon, and stored in a slide cassette, the method comprising: (a)determining the number and position of microscope slides stored incassette; (b) causing one or more of slides in cassette to be removedfrom cassette; (c) downloading encoded data on each of slide(s) removedfrom cassette; (d) associating downloaded encoded data with a setprotocol for analysis of material on microscope slide. The encoded datamay comprise data physically stored on the slide, or in electronicsassociated with the slide.

In order to improve efficiency in the microscopic read, slides may bestored in a slide magazine or cassette. The magazine may be an improvedmagazine 10 allowing for the ease of withdrawal of the slide from themagazine. For example, the slide magazine may comprise a housing havinga top wall 20, a bottom wall 30, a first side wall 40 and a second sidewall 50 configured as a rectangular box-like structure enclosing a void70 having a forward edge 80 and a rearward edge 90. Each wall of thestructure has an inner surface facing the void and an outer surfacefacing outward. The inner surface of the first side wall 40 incorporatesa plurality of equally spaced rails 100 parallel to the bottom wallextending generally from the forward edge 80 to the rearward edge 90.The second side wall 110 is partially cut with equally spaced slots 120,parallel to the bottom wall 30 forming flexible fingers 130, extendingfrom the forward edge 80 partially to the rearward edge 90. The innersurface of the second side wall 50 incorporates a second set of rails140 which are co-planar to the rails 100 located on the first side wall.Each of the second side wall rails 140 may be incorporated, in part,into one of the flexible fingers 130. The spacing between the first sidewall 40 and second side wall 50 inner surfaces is selected so that whena microscope slide is inserted into magazine 10, so as to sit on thecorresponding first 100 and second 140 wall surface rails, therespective flexible finger 130 is displaced resulting in the applicationof a securing force on the slide. The second side wall 50 may optionallyalso be partially cut to result in a second set of equally spaced slots150, in co-planar alignment with the first set of slots 120, parallel tothe bottom wall 30 forming flexible fingers 160, extending from therearward edge 90 partially to the forward edge 80. The flexible fingers130,160 structure may provide for click lock of the microscope slideinto its respective parking position. Thus dislodgement of themicroscope slides from the magazine may be prevented irrespective ofspatial orientation.

In operation, the microscope slide is placed entirely within said voidbetween a spaced rail of said inner surface of said first side wall anda spaced rail of said inner surface of said second side wall, saidmicroscope slide is locked in place within the magazine by a snap-fitengagement structure associated with at least one flexible finger. Oneexample of a snap-fit engagement structure is a discontinuity on thesurface of the finger.

When slides are stored in magazines 10 or cassettes and themagazines/cassettes are loaded onto an automated microscopy system, itis advantageous that the microscopy system have a slide feeder that isoptimized for the magazine/cassette.

In one embodiment of the invention, the slides are removed from themagazine 10 by a slide feeder (not shown) that removes the slide fromthe magazine 10 by grabbing the slide along the two lateral surfaces ofthe slide, that is, holding the slide by pressure fit at the slides.Such system is advantageous in that it reduces the risks of introducingartifacts into the sample view (e.g. by scratching the slide frombeneath, adding dust to the portion of the slide to be read etc.). Inone embodiment, there is disclosed a slide feeder for moving a slidehaving a top surface, a bottom surface and two or more lateral sidesurfaces(s) from a first location to a second location, the slide feedercomprising: (a) a stage operatively configured to move in an x-ydirection; and a slide engager coupled to the stage, the slide engageroperatively configured to hold the slide by pressure fit between two ormore lateral surfaces of the slide.

The slide feeder may then position the slide for read in the stage Inone embodiment, there is provided a microscope for reading a microscopeslide, the microscope comprising: (a) a first stage operativelyconfigured to hold a microscope slide and to move only along an x-yaxis; (b) a second stage operatively associated with the first stagecapable of movement only along the z axis; wherein movement of thesecond stage along such axis causes movement of the microscope slideheld by the first stage in the same direction.

Particularly when automated microscopy is employed wherein the system isdesigned to provide an automated diagnosis with respect to a tissuesample from a patient, it is advantageous to obtain multiple images of asample. In one embodiment, there is provided microscope slide imagecapture system comprising: (a) a camera having at least one CMOSdetector (or other suitable imaging detector such as, for example, CCD)and operatively configured to capture, for example, at least about 300or more images per second; (b) a plurality of sensors positioned todetect movement of the microscope slide in x-y-z space during capture ofeach image; and a processor operatively configured to process imagesfrom the camera and data from the plurality of sensors and to correctfor movement of images during image capture by either altering theimages or discarding the same.

Images obtained may be displayed in numerous manners to a microscopistinterested in reviewing the images, in particular to confirm thetentative diagnosis of an automated microscopy system. In oneembodiment, there is disclosed a graphical user interface in amicroscopy system comprising: (a) a first portion graphically displayingthe surface of a microscope slide and the relative position of field ofinterest thereon; (b) a second portion graphically displaying the fieldof interest in a plurality of magnifications; wherein the first andsecond graphical displays are movable at least along the x and y axis.

In an embodiment, a processor configured for processing information fromsaid detector and said field objective may be employed to determine theposition of the field viewed or desired to be marked with respect to atleast one of the said electronically-addressable position tag(s). Theprocessor may also write the position of the field desired to be markedin response to said reference position tag in electronic data memoryassociated with said slide. The processor may further write the image ofthe microscope field to said electronic data memory associated with saidslide.

Once images are evaluated, it may be useful clinically to once more viewthe particular slide, which is the basis of the tentative diagnosis. Inorder to home back into the particular cell or area of the slide, whichraises suspicions, it is useful to have a system that allows for rapidpinpointing of the exact cell or area. One method for doing so, proposedherein, utilizes one or more tags on the microscope slide, which act asreference point(s) on the slide to provide for “GPS-like” repositioningof the objective of the microscope with the particular area on the slideto be viewed. The reference tags should be automatically detectable andbe correlated with a particular reference position on the slide. Bycalculating position of each image with respect to one or more such tagson the slide, and storing the same with the image, one can quicklyreturn to the original field of view on the slide. This eliminates theneed to repeat the search over the entire specimen to locate the fieldof interest.

In one embodiment there is disclosed an automated microscope slideanalysis system for viewing microscope slides, the system comprising:(a) one or more microscope slides having one or moreelectronically-addressable position tag(s) thereon; (b) a fieldobjective operatively configured to allow viewing of a defined field onmicroscope slide; (c) an emitter operatively configure to emit anelectromagnetic wave toward at least one of electronically-addressableposition tag(s); (d) a detector operatively configured to detect atleast one of position tag(s) from the response of the tag to theelectromagnetic wave; and a processor configured for processinginformation form the detector and the field objective to determine theposition of the field viewed or desired to be marked with respect to atleast one of the electronically-addressable position tag(s).

STATEMENT REGARDING PREFERRED EMBODIMENTS

While the invention has been described with respect to preferredembodiments, those skilled in the art will readily appreciate thatvarious changes and/or modifications can be made to the inventionwithout departing from the spirit or scope of the invention as definedby the appended claims. All documents cited herein are incorporated byreference herein where appropriate for teachings of additional oralternative details, features and/or technical background.

1. A microscope slide magazine comprising: a housing having a top wall,a bottom wall, a first side wall and a second side wall configured as arectangular box-like structure enclosing a void and having a forwardedge and a rearward edge; each wall of said rectangular box-likestructure having an inner surface facing the said void and an outersurface facing outward; said inner surface of the first side wallincorporating a plurality of equally spaced rails parallel to the bottomwall extending generally from said forward edge to said rearward edge;said second side wall having a set of partially cut equally spacedslots, parallel to the bottom wall forming flexible fingers, extendingfrom the said forward edge partially to the said rearward edge; saidinner surface of the said second side wall incorporating a second set ofrails positioned to be co-planar to the said rails located on the innersurface of said first side wall, each of the said second side wall railsbeing incorporated into one of the said flexible fingers; spacingbetween the said first and said second side wall inner surfaces isconfigured so that when microscope slide is inserted into the saidmagazine, the respective said flexible finger is displaced.
 2. Amicroscope slide magazine of claim 1 where said microscope slide isplaced entirely within said void between a spaced rail of said innersurface of said first side wall and a spaced rail of said inner surfaceof said second side wall, said microscope slide is locked in placewithin the magazine by a snap-fit engagement structure associated withat least one flexible finger.
 3. The microscope slide magazine of claim2 wherein said snap-fit engagement structure of said at least oneflexible finger is a discontinuity on the surface of the flexiblefinger.
 4. A microscope slide magazine of claim 1 where the said secondside wall comprises a second set of partially-cut equally spaced slots,parallel to the bottom wall forming flexible fingers, extending from thesaid rearward edge partially to the said forward edge.
 5. A microscopefor reading a microscope slide, said microscope comprising: a firststage operatively configured to hold a microscope slide and to move onlyalong an the x-y axis; a second stage operatively associated with saidfirst stage and capable of movement only along the z⁻-z⁺ axis; whereinsaid movement of said second stage along such axis causing movement ofsaid microscope slide held by said first stage in the same direction. 6.A slide feeder for moving a slide, from a first location to a secondlocation, said slide comprising a substrate having a top surface, abottom surface and two or more lateral side surfaces from a firstlocation to a second location, said slide feeder comprising: a stageoperatively configured to move in an x-y direction; a slide engagercoupled to said stage, said slide engager operatively configured to holdsaid slide by pressure fit between two or more lateral side surfaces ofsaid slide.
 7. A method in a computer system for automating microscopicanalysis of a plurality of data-encoded microscope slides havingmaterial of analytical interest deposited thereon, and stored in a slidecassette, the method comprising: determining the number and position ofeach of said microscope slides stored in said cassette; causing on ormore of said slides in said cassette to be removed from said cassette;downloading the encoded data on each of said slide(s) removed from saidcassette; associating said downloaded encoded data with a set protocolfor analysis of said material on said microscope slide.
 8. A microscopeslide comprising: a substrate configured for carrying a specimenobtained from a larger body; a data memory affixed to said substrate;said data memory housing data related to a protocol for examination ofsaid specimen to determine a state of said larger body; wherein saiddata may be retrieved from said data memory by a data reader.
 9. Amicroscope slide as in claim 8 where said data memory is a write-onceread-many (WORM) memory.
 10. A microscope slide comprising: a substrateconfigured for carrying a specimen obtained from a larger body; a datamemory affixed to said substrate; said data memory housing image dataobtained from microscopic examination of said specimen at one or morepoints in time.
 11. A microscope slide as in claim 10 where said datamemory is a write-once read-many (WORM) memory.
 12. A microscope slidecomprising: a substrate configured for carrying a biological specimenobtained from a patient; a data memory affixed to said substrate; saiddata memory housing data pertaining to the name, age, and medicalhistory of said patient.
 13. A microscope slide as in claim 12 wheresaid data memory is a write-once read-many (WORM) memory.
 14. Amicroscope slide image capture system: a camera having at least oneimage detector and operatively configured to capture multiple images persecond; a plurality of sensors operatively configured to detect movementof said microscope slide in x-y-z space during capture of each image; aprocessor operatively configured to process images from said camera anddata from said plurality of sensors and to correct for movement ofimages during image capture by either altering said images or discardingthe same.
 15. A microscope slide image capture system of claim 14wherein the said camera has at least one CMOS detector.
 16. A microscopeslide image capture system of claim 14 wherein the said camera has atleast one CCD detector.
 17. A microscope slide image capture system ofclaim 14 wherein said camera is operatively configured to capture atleast about 300 or more images per second.
 18. A graphical userinterface in a microscope system comprising: a first portion graphicallydisplaying the surface of a microscope slide and the relative positionof fields of interest thereon; a second portion graphically displayingsaid fields of interest in a plurality of magnifications; wherein saidfirst and second graphical displays are movable in at least along the xand y axis.
 19. An automated microscope slide analysis system forviewing microscope slides, said system comprising: one or moremicroscope slides each having one or more electronically-addressablereference position tag(s) thereon; a field objective operativelyconfigured to allow viewing of a defined field on said microscope slide;an emitter operatively configured to emit an electromagnetic wave towardat least one of said electronically-addressable reference positiontag(s); a detector operatively configured to detect said position tagfrom response of said position tag to said electromagnetic wave; and aprocessor configured for processing information from said detector andsaid field objective to determine the position of the field viewed ordesired to be marked with respect to at least one of the saidelectronically-addressable position tag(s), and to cause writing of saidposition of said field desired to be marked in response to saidreference position tag in electronic data memory associated with saidslide.
 20. An automated microscope analysis system of claim 19 whereinsaid processor is further configured to cause writing of an image tosaid electronic data memory associated with said slide.